Successful treatment of cocaine dependence must involve the prevention of environmentally-induced cocaine relapse. Drug-context-induced cocaine relapse relies on the utilization of long-term memories of context- response-cocaine associations. These associative memories can become labile upon retrieval, and must undergo protein synthesis-dependent re-stabilization (i.e., reconsolidation) in order to be maintained in long- term memory. Abnormally enhanced memory reconsolidation may contribute to intrusive thoughts about cocaine and strong cue reactivity, which are the hallmarks of drug addiction. Hence, manipulations that disrupt cocaine memory reconsolidation or inhibit pathological cocaine memories are of tremendous interest from an addiction treatment perspective. Understanding the putative relationship between pathological cocaine memory reconsolidation and drug relapse is a complex problem that requires a two-part approach: (1) identification of the neurobiological substrates of memory reconsolidation that promote drug-context-induced drug seeking and (2) discovery of pathology within these substrates. Focusing on the first objective, the overarching goal of this project is to elucidate essential, and previously uncharacterized, functional neuroanatomical and cellular mechanisms of memory reconsolidation that facilitate drug-context-induced instrumental cocaine seeking. The project will rely upon our previous work, which has demonstrated that protein synthesis in the basolateral amygdala (BLA) and the functional integrity of the dorsal hippocampus (DH) are necessary for cocaine memory reconsolidation and subsequent drug-context-induced cocaine seeking in rats. However, it is unclear whether there is obligatory interaction between these brain regions. Thus, Aim 1 will be to begin to map the putative cocaine memory reconsolidation circuitry. Experiments will test the hypothesis that sequential information processing by the DH and BLA is required for cocaine memory reconsolidation that facilitates subsequent context-induced cocaine seeking. Additional experiments will evaluate whether the nucleus accumbens core and shell, two efferents of the above brain regions, are a part of this circuitry. Based on our previous work, Aim 2 will center on putative cellular mechanisms of cocaine memory reconsolidation in the BLA. It has been postulated that cocaine-induced neuroplasticity, notably enhanced cAMP- and Ca2+ dependent cellular signaling, may trigger pathological memory reconsolidation. To examine two basic assumptions of this idea, experiments will test the hypothesis that (A) the activity of these pathways in the BLA is necessary for cocaine memory reconsolidation and that (B) mimicking the increase in the activity of these signaling pathways putatively produced by chronic cocaine administration is sufficient to potentiate cocaine memory reconsolidation and context-induced cocaine seeking. In sum, this project will explore the neurobiology of cocaine memory reconsolidation to provide a rationale for future research into pathological cocaine memory reconsolidation and for the development of novel pharmacotherapies for drug addiction.